Pre-marketing clinical trials show that antidepressant-induced liver injury seems to be a rare adverse event. Because of short follow-up trial duration, the incidence of liver injury due to antidepressant use could be underestimated.
We aimed to quantify the risk of acute liver injury associated with antidepressant use through a case–control analysis among an inpatient population.
A multicenter study was carried out in nine Italian hospitals from October 2010 to January 2014, within the DILI-IT (Drug-Induced Liver Injury in Italy) study project. After exclusion of all patients with a clear competing cause of liver injury, cases were defined as adults admitted to the hospital with a diagnosis of acute liver injury, while controls had any other acute clinical condition not related to the liver. Antidepressant exposure was evaluated within 90 days prior to the date of the first sign/symptom of liver injury. Odds ratio (OR) with 95% confidence interval (95% CI) was calculated as a measure of risk estimates for liver injury.
We included 17 cases exposed to antidepressants matched to 99 controls. According to the features of liver injury, all cases showed symptomatic liver function test abnormalities at hospital admission, with the main signs/symptoms represented by fatigue, nausea, asthenia, or dark urine. Citalopram was the antidepressant mostly involved in the increase of liver enzymes, mainly alanine aminotransferase. Compared with non-use, current use of antidepressants was associated with a significantly increased risk of liver injury (adjusted OR, ORADJ, 1.84; 95% CI 1.02–3.32). Specifically, an increased, but not significant, risk of developing liver injury was observed for citalopram, a selective serotonin-reuptake inhibitor (ORADJ 1.82; 95% CI 0.60–5.53).
The use of antidepressants is not as safe in terms of liver injury as expected; instead, the risk of antidepressant-induced liver injury is likely underestimated. The lack of significance does not reflect the absence of risk, but rather suggests the need to evaluate it in a wider setting of antidepressant users.
This is a preview of subscription content, access via your institution.
Buy single article
Instant access to the full article PDF.
Price excludes VAT (USA)
Tax calculation will be finalised during checkout.
Voican CS, Corruble E, Naveau S, et al. Antidepressant-induced liver injury: a review for clinicians. Am J Psychiatry. 2014;171(4):404–15.
DeSanty KP, Amabile CM. Antidepressant-induced liver injury. Ann Pharmacother. 2007;41(7):1201–11.
Conway CR, McGuire JM, Baram VY. Nefazodone-induced liver failure. J Clin Psychopharmacol. 2004;24(3):353–4.
Suen CF, Boyapati R, Simpson I, et al. Acute liver injury secondary to sertraline. BMJ Case Rep. 2013;2013:1–5. doi:10.1136/bcr-2013-201022.
Yildirim B, Tuncer C, Ergun M, et al. Venlafaxine-induced hepatotoxicity in a patient with ulcerative colitis. Ann Hepatol. 2009;8(3):271–2.
Sgro C, Clinard F, Ouazir K, et al. Incidence of drug-induced hepatic injuries: a French population-based study. Hepatology. 2002;36(2):451–5.
Carvajal Garcia-Pando A, Garcia del Pozo J, Sanchez AS, et al. Hepatotoxicity associated with the new antidepressants. J Clin Psychiatry. 2002;63(2):135–7.
Ferrajolo C, Capuano A, Verhamme KM, et al. Drug-induced hepatic injury in children: a case/non-case study of suspected adverse drug reactions in VigiBase. Br J Clin Pharmacol. 2010;70(5):721–8.
Ferrajolo C, Coloma PM, Verhamme KM, et al. Signal detection of potentially drug-induced acute liver injury in children using a multi-country healthcare database network. Drug Saf. 2014;37(2):99–108.
Donati M, Conforti A, Lenti MC, et al. Risk of acute and serious liver injury associated to nimesulide and other NSAIDs: data from drug-induced liver injury case-control study in Italy. Br J Clin Pharmacol. 2016;82(1):238–48.
Benichou C. Criteria of drug-induced liver disorders. Report of an international consensus meeting. J Hepatol. 1990;11(2):272–6.
Ferrajolo C, Verhamme KM, Trifiro G, et al. Idiopathic acute liver injury in paediatric outpatients: incidence and signal detection in two European countries. Drug Saf. 2013;36(10):1007–16.
Ferrajolo C, Verhamme KM, Trifiro G, et al. Antibiotic-induced liver injury in paediatric outpatients: a case-control study in primary care databases. Drug Saf. 2017;40(4):305–15.
Traversa G, Bianchi C, Da Cas R, et al. Cohort study of hepatotoxicity associated with nimesulide and other non-steroidal anti-inflammatory drugs. BMJ. 2003;327(7405):18–22.
Bjornsson ES. Drug-induced liver injury: an overview over the most critical compounds. Arch Toxicol. 2015;89(3):327–34.
Lee WM. Drug-induced hepatotoxicity. N Engl J Med. 2003;349(5):474–85.
Brauer R, Douglas I, Garcia Rodriguez LA, et al. Risk of acute liver injury associated with use of antibiotics. Comparative cohort and nested case-control studies using two primary care databases in Europe. Pharmacoepidemiol Drug Saf. 2016;25(Suppl 1):29–38.
Ruigomez A, Brauer R, Rodriguez LA, et al. Ascertainment of acute liver injury in two European primary care databases. Eur J Clin Pharmacol. 2014;70(10):1227–35.
Friedrich ME, Akimova E, Huf W, et al. Drug-induced liver injury during antidepressant treatment: results of AMSP, a drug surveillance program. Int J Neuropsychopharmacol. 2016;19(4):1–9.
Carvalho AF, Sharma MS, Brunoni AR, et al. The safety, tolerability and risks associated with the use of newer generation antidepressant drugs: a critical review of the literature. Psychother Psychosom. 2016;85(5):270–88.
Azaz-Livshits T, Hershko A, Ben-Chetrit E. Paroxetine associated hepatotoxicity: a report of 3 cases and a review of the literature. Pharmacopsychiatry. 2002;35(3):112–5.
Colakoglu O, Tankurt E, Unsal B, et al. Toxic hepatitis associated with paroxetine. Int J Clin Pract. 2005;59(7):861–2.
Helmchen C, Boerner RJ, Meyendorf R, et al. Reversible hepatotoxicity of paroxetine in a patient with major depression. Pharmacopsychiatry. 1996;29(6):223–6.
Odeh M, Misselevech I, Boss JH, et al. Severe hepatotoxicity with jaundice associated with paroxetine. Am J Gastroenterol. 2001;96(8):2494–6.
Pompili M, Tittoto P, Masciana R, et al. Acute hepatitis associated with use of paroxetine. Intern Emerg Med. 2008;3(3):275–7.
Benbow SJ, Gill G. Paroxetine and hepatotoxicity. BMJ. 1997;314(7091):1387.
Chu AG, Gunsolly BL, Summers RW, et al. Trazodone and liver toxicity. Ann Intern Med. 1983;99(1):128–9.
Fernandes NF, Martin RR, Schenker S. Trazodone-induced hepatotoxicity: a case report with comments on drug-induced hepatotoxicity. Am J Gastroenterol. 2000;95(2):532–5.
Hull M, Jones R, Bendall M. Fatal hepatic necrosis associated with trazodone and neuroleptic drugs. BMJ. 1994;309(6951):378.
Longstreth GF, Hershman J. Trazodone-induced hepatotoxicity and leukonychia. J Am Acad Dermatol. 1985;13(1):149–50.
Rettman KS, McClintock C. Hepatotoxicity after short-term trazodone therapy. Ann Pharmacother. 2001;35(12):1559–61.
Conrad MA, Cui J, Lin HC. Sertraline-associated cholestasis and ductopenia consistent with vanishing bile duct syndrome. J Pediatr. 2016;169(313–5):e1.
Collados V, Hallal H, Andrade RJ. Sertraline hepatotoxicity: report of a case and review of the literature. Dig Dis Sci. 2010;55(6):1806–7.
Solomons K, Gooch S, Wong A. Toxicity with selective serotonin reuptake inhibitors. Am J Psychiatry. 2005;162(6):1225.
Ma L, Wen C, Chen C, et al. Hepatotoxicity associated with donepezil in an individual taking citalopram. J Am Geriatr Soc. 2016;64(5):1144–5.
Danan G, Bernuau J, Moullot X, et al. Amitriptyline-induced fulminant hepatitis. Digestion. 1984;30(3):179–84.
Yon J, Anuras S. Hepatitis caused by amitriptyline therapy. JAMA. 1975;232(8):833–4.
Larrey D, Amouyal G, Pessayre D, et al. Amitriptyline-induced prolonged cholestasis. Gastroenterology. 1988;94(1):200–3.
Andrade RJ, Lucena MI, Fernandez MC, et al. Drug-induced liver injury: an analysis of 461 incidences submitted to the Spanish registry over a 10-year period. Gastroenterology. 2005;129(2):512–21.
Licata A, Minissale MG, Calvaruso V, et al. A focus on epidemiology of drug-induced liver injury: analysis of a prospective cohort. Eur Rev Med Pharmacol Sci. 2017;21(1 Suppl):112–21.
Bjornsson ES. Hepatotoxicity by drugs: the most common implicated agents. Int J Mol Sci. 2016;17(2):224.
Voican CS, Martin S, Verstuyft C, et al. Liver function test abnormalities in depressed patients treated with antidepressants: a real-world systematic observational study in psychiatric settings. PLoS One. 2016;11(5):e0155234.
Gahr M, Zeiss R, Lang D, et al. Drug-induced liver injury associated with antidepressive psychopharmacotherapy: an explorative assessment based on quantitative signal detection using different MedDRA terms. J Clin Pharmacol. 2016;56(6):769–78.
We are grateful for the help and support of the DILI-IT Study Group, which includes the following clinical investigators: Franco Capra, Angelo Tonon, University Hospital of Verona; Marco Zoli, University Hospital S. Orsola-Malpighi of Bologna and the Head of each Internal Medicine, Geriatric, and other participating units; Enrica Cecchi, Stefano Grifoni, Careggi Hospital of Florence; Fulvio Calise, Cardarelli Hospital of Naples; Pietro Amoroso, Cotugno Hospital of Naples; Evangelista Sagnelli, San Sebastiano Hospital of Caserta; Annamaria Frola, Umberto I Hospital Unit of Salerno. Study monitors: Elena Arzenton, Giovanna Stoppa, Verona; Maria Carmela Lenti, Roberto Bonaiuti, Florence; Carolina Tiani, Bologna; Carla Migliaccio, Andrea Vitale, Nancy Acampa, Naples. Steering Committee: Nicola Montanaro, University of Bologna; Francesco Lapi and Alessandro Mugelli, University of Florence; Francesco Rossi, University of Naples. Data manager: Giulia Bisoffi, University Hospital of Verona. We thank the members of the External Advisory Board: Maria Grazia Franzosi, Nicola Magrini, Luigi Pagliaro, Giuseppe Traversa, and Mauro Venegoni.
This study was funded by the Italian Medicines Agency (AIFA), through a call for independent research (ID Study FARM8B2TY7). All institutions received financial support from AIFA for the research study; there are no financial relationships with any organizations that might have an interest in the submitted work in the previous three years.
Conflict of interests
Carmen Ferrajolo, Cristina Scavone, Monia Donati, Oscar Bortolami, Giovanna Stoppa, Domenico Motola, Alfredo Vannacci, Alessandro Mugelli, Roberto Leone, and Annalisa Capuano have no conflicts of interest that are directly relevant to the content of this study.
The study protocol was independently approved by ethics committees for each participant hospital.
Each patient was informed about the aim of the study and written informed consent was signed before the interview.
Electronic supplementary material
Below is the link to the electronic supplementary material.
Rights and permissions
About this article
Cite this article
Ferrajolo, C., Scavone, C., Donati, M. et al. Antidepressant-Induced Acute Liver Injury: A Case–Control Study in an Italian Inpatient Population. Drug Saf 41, 95–102 (2018). https://doi.org/10.1007/s40264-017-0583-5